Gabapentin (1-(aminomethyl)cyclohexane acetic acid) is a 3-substituted γ-aminobutyric acid (“GABA”) analog that was approved in the United States on Dec. 30, 1993 as NEURONTIN® (Pfizer Inc., New York, N.Y.), an immediate release dosage form of gabapentin for use as adjunctive therapy in the treatment of partial seizures in children and adults, and was subsequently approved for treatment of post-herpetic neuralgia (“PHN”) in adults. In addition to seizures and PHN, gabapentin has also been used in the treatment of neuropathic pain, restless legs syndrome, essential tremor, bipolar disorder, migraine headaches, and the symptoms associated with menopause, hormonal imbalances, and chemotherapy. Magnus et al., EPILEPSIA 40:S66-S72 (1999); U.S. Pat. No. 6,310,098 to Guttuso. Gabapentin is currently available as immediate release NEURONTIN® in 100 mg, 300 mg, and 400 mg hard shell capsules; 600 mg and 800 mg film-coated tablets; and in a liquid formulation having 250 mg/5 mL. The recommended dosage for gabapentin is a total daily dose of 900 mg to 1800 mg t.i.d. (i.e., three times daily).
In humans, gabapentin is absorbed throughout the small intestine with diminished absorption in the colon. The absorption of immediate release gabapentin occurs relatively slowly with the peak plasma concentration occurring approximately 2 to 3 hours after dosing. The oral bioavailability of gabapentin is dose-dependent, with approximately 60% bioavailability for a dose in the range of 300-400 mg, but with only 35% bioavailability for a dose of 1600 mg. Bourgeois, EPILEPSIA 36 (Suppl. 5):S1-S7 (1995); Gram, EPILEPSIA 37 (Suppl. 6):S12-S16 (1996); DRUGS OF TODAY 31:613-9:975-82 (1995); NEUROLOGY 44(Suppl. 5): S17-S32 (2003). The decrease in bioavailability with increasing dose of the immediate release tablet has been attributed to partially carrier-mediated absorption. Stewart, et al., PHARMACEUTICAL RESEARCH 10(2):276-281 (1993).
Food has only a small effect on the rate and extent of immediate release gabapentin absorption. Further, only 3% of circulating gabapentin is bound to plasma proteins. Gabapentin is not appreciably metabolized in humans, does not induce hepatic enzymes, and is eliminated unchanged by renal excretion with a half-life of 5-7 hours regardless of whether the drug is taken in a single dose or in multiple doses. (Chadwick; LANCET 343:89-91 (1994); Thomson, et al., CLIN. PHARMACOKINET. 23(3):216-230 (1992); and Riva, et al., CLIN. PHARMACOKINET. 3 1(6):470-493 (1996)).
Because gabapentin is administered t.i.d., patient compliance with the conventional immediate release dosage forms of the drug is an issue. In this respect, controlled release dosage forms that would lower the number of daily dosings of gabapentin to once-daily or twice-daily dosings would provide a significant advantage over the conventional immediate release dosage form; however, in order for the controlled release dosage form to be effective, the dosage form must overcome the poor absorption of the drug in the lower gastrointestinal tract.
In addition to the compliance and bioavailability issues associated with the conventional immediate release dosage form of gabapentin, gabapentin use also suffers from the adverse side effects associated with the drug. Side effects reported from gabapentin use include, most commonly, somnolence and dizziness, and to a lesser degree, fatigue, ataxia, weight gain, peripheral edema, diarrhea, headache, dry mouth, and blurred vision. More recently, gabapentin use has been associated with the serious side effect of reversible visual field constriction. Bekkelund et al., BRIT. MED. J 323:1193 (2006).
The issue of gabapentin side effects has become increasingly troublesome since gabapentin was found to reduce the frequency and severity of hot flashes in menopausal women. U.S. Pat. No. 6,310,098 to Guttuso. As a result of the prevalence of the somnolence and dizziness side effects, many women who have been taking gabapentin for treatment of their menopausal symptoms have been forced to discontinue use of the drug.
In order for gabapentin to gain widespread acceptance for current, i.e., epilepsy and post-herpetic neuralgia, and future off-label uses, such as, for example, restless-leg syndrome, diabetic neuropathy, back pain, essential tremor, bipolar disorder, migraine prophylaxis, potentially alcohol and drug withdrawal, and the symptoms associated with menopause, hormonal imbalances, and chemotherapy, there is a need in the art for an improved dosage form of gabapentin that may be administered once or twice daily with sufficient absorption of the active agent to produce the desired therapeutic effects while increasing the bioavailability of the drug at elevated doses and reducing the side effects associated with the drug at the therapeutic dosages.
Examples of modified release dosage forms, such as controlled-release dosage forms, sustained release dosage forms, and extended release dosage forms are known in the art to which the invention pertains; however, to the best of the inventor's knowledge, gabapentin has not been successfully incorporated into any modified release dosage form because the pharmacokinetics of the drug does not facilitate the absorption of the drug in modified release dosage forms. In fact, the innovator noted in the Summary Basis of Approval (NDA 20-235), that a pilot study (Study #877-076) of a 600 mg sustained release formulation “indicated unacceptable sustained release characteristics,” (NDA 20-235) which was attributed to decreasing rate and extent of absorption as gabapentin “moves lower in the GI tract.” (NDA 20-235). In order to overcome the shortcomings inherent in the immediate delivery dosage forms of gabapentin, a gastric retentive dosage form of gabapentin would allow for sustained release of gabapentin while avoiding the significant loss of bioavailability of the drug observed with non-gastric retentive controlled release dosage forms.
Pain management continues to be a challenge for medical practitioners. Many pain medications have unfavorable side effects. In addition, patients can develop tolerance to pain medications and require larger doses to reach a previously achieved level of pain relief.
Pain is generally classified as either nociceptive pain or non-nociceptive pain. Nociceptive pain arises from the stimulation of pain receptors (i.e., nociceptive receptors) to heat, cold, vibration, stretch, and chemical stimulus from damaged cells. Somatic pain (i.e., musculoskeletal pain, such as pain specific to skin, muscle, joints, bones, and ligaments) and visceral pain (i.e., pain specific to the internal organs and main body cavities) are the two types of nociceptive pain. Nociceptive pain is usually time-limited and thus, when the tissue heals, the pain is resolved. During periods of pain, nociceptive pain responds well to treatment with opioids.
Non-nociceptive pain arises from within the peripheral and central nervous system, where there are no pain receptors. The pain associated with non-nociceptive pain is generated from nerve cell dysfunction. Non-nociceptive pain includes neuropathic pain and sympathetic pain.
Neuropathic pain originates in the peripheral nervous system (the nerves between the tissue and the spinal cord) or the central nervous system (the nerves between the spinal cord and the brain). Neuropathic pain may be caused by nerve degeneration (e.g., by multiple sclerosis), nerve pressure (e.g., from a trapped nerve); nerve inflammation (e.g., from a torn or slipped disc), or nerve infection (e.g., from shingles or other viral infections). With neuropathic pain, the injured nerves become electrically unstable firing of signals in an inappropriate, random, and disordered fashion. Neuropathic pain is characterized by nerve malfunctions such as hypersensitivity to touch, vibrations, and extreme temperatures and is often described as burning, lancinating, and shooting pain.
Sympathetic pain is caused from possible over activity of the sympathetic system, which controls blood flow to tissues such as skin and muscle, sweating by the skin, and the speed and responsiveness of the peripheral nervous system. Sympathetic pain occurs most commonly after fractures and soft tissue injuries of the arms and legs. Sympathetic pain is characterized by extreme sensitivity in the skin surrounding the site of injury and peripherally in the afflicted limb, which may become so painful that the patient will refuse to use it causing secondary problems with the limb due to non-use.
Unlike nociceptive pain is not time limited and is not easily treatable. Non-nociceptive pain is generally treated with anti-depressants, anti-convulsants (i.e., anti-epileptic drugs), and anti-arrhythmics; however, to date, there is no effective treatment for non-nociceptive pain. In commonly owned co-pending U.S. patent application Ser. No. 10/280,309 (Publication No. US 2003/0100611 A1), the present inventors disclosed a gastric-retentive form of gabapentin and the use of the drug for the treatment of neuropathic pain, which is a non-nociceptive pain state.
An osmotic dosage form has been described for delivery of gabapentin prodrugs. U.S. Pat. No. 6,683,112 to Chen at al. describes sustained release formulations that deliver gabapentin prodrugs by means of the push-pull osmotic pump system described in U.S. Pat. No. 4,612,008 to Wong et al. This system however, is not a gastric retentive dosage form and would be expected to deliver the drug with poor bioavailability.
Examples of gastric retentive dosage forms are described in U.S. Pat. No. 4,996,058 to Sinnreich; U.S. Pat. No. 5,232,704 to Franz et al.; U.S. Pat. No. 6,120,802 to Wong et al.; and commonly owned U.S. Pat. No. 5,972,389 to Shell et al. and PCT Publication No. WO 98/055107 to Depomed, Inc. None of these references, however, teach or suggest the use of the gastric retentive dosage forms described therein for the administration of gabapentin. To the best of the inventors' knowledge, a dosing regimen using a gastric retentive dosage form of gabapentin for reducing or eliminating side effects associated with gabapentin treatment has not been previously described. Further, to the best of the inventors' knowledge, a dosing regimen using a gastric retentive dosage form of gabapentin for pain treatment has not been previously described.
The present invention overcomes the need in the art for a more effective gabapentin dosage form that will increase patient compliance and provide for extended effective plasma levels so that patients suffering from a non-nociceptive pain state may be able to more effectively use gabapentin for treatment of pain symptoms.